HK1082735B - Process for preparing the calcium salt of rosuvastatin - Google Patents

Description

Process for preparing rosuvastatin calcium salt

The present invention relates to an improvement in the chemical process, in particular a chemical process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt (as shown in the following figure) useful in the preparation of medicaments useful, inter alia, for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

European patent 0521471 discloses the compound (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid (hereinafter referred to as "drug") and its sodium and calcium salts. The patent also describes a method for synthesizing the calcium salt of the drug, the final step of which is to convert the sodium salt of the drug to the calcium salt. The resulting calcium salt is then collected and dried, and may be further processed as desired.

This method of converting the sodium salt to the calcium salt and then collecting the resulting calcium salt and drying is also described in our international patent application WO 00/49014.

The methods described in the above two patent documents include the steps of: adding dropwise an aqueous solution of calcium chloride to the aqueous solution of the sodium salt at 20 ℃, stirring the resulting mixture for, for example, 45 minutes, and then separating the product precipitate by filtration; washing the filtered product and drying at 40 ℃ under reduced pressure; extensive washing is required to ensure removal of sodium chloride as a reaction by-product; filtration and drying are then required to render the final product suitable for use as a pharmaceutical.

According to the processes described in these patent applications, precipitation at 20 ℃ may give the product a physical form which is difficult and slow (i.e. inefficient) to filter, and which retains a large amount of water after filtration. Further drying is necessary to obtain a final product suitable for use as a pharmaceutical. Although bench (laboratory), pilot scale, operable, at production scale, the operation of the product requiring such treatment is very problematic and not satisfactory in terms of yield and potential product quality.

We have found a surprising improved process for preparing the calcium salt which results in improved filtration efficiency of the product during the separation process.

Generally, an indication of increased filtration efficiency is that more solvent, such as water, is removed from the product during filtration, thereby allowing faster filtration. It will be appreciated that in general, to achieve the same goal, a product containing a small amount of solvent (e.g., water) after isolation will require less drying time than a product containing a higher amount of solvent. It will also be appreciated that efficient filtration during the initial separation of the product has advantages over filtration as part of a subsequent washing process.

Therefore, it can be understood that the method of the present invention has significant manufacturing advantages, such as increased yield.

Accordingly, the present invention provides an improved process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, the process comprises mixing a solution of calcium chloride with a solution of a water-soluble salt of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid, wherein the process parameters are selected such that the resulting product exhibits characteristics of improved filtration efficiency.

Suitable water-soluble salts may be metal salts, for example the following alkali metal salts, such as sodium, lithium or potassium; or an ammonium salt or an organic amine salt such as methylamine or TRIS (hydroxymethyl) methylamine). Preferred salts are sodium, potassium and ammonium salts. Further preferred salts are ammonium, methylamine and TRIS salts. TRIS salts are even more preferred. Most preferred is the sodium salt.

For the avoidance of doubt, the water-soluble salt solution may be prepared by dissolving the salt in solid form in water. Alternatively, the water-soluble salt solution may be formed from (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid or a suitable derivative thereof, for example other salt forms. For example, when the water-soluble salt is a sodium salt, it may be produced by treating other salts (in solid form or in suspension or aqueous solution) such as an amine salt (e.g. ammonium or methylamine salt) with a sodium base such as sodium carbonate or sodium hydroxide, preferably sodium hydroxide. Aqueous sodium base solutions are more convenient. Similarly, other bases, such as other alkali metal bases, can be used to prepare other water-soluble salt solutions.

In general, the calcium chloride solution should be an aqueous solution or substantially an aqueous solution. Typically the water-soluble salt solution should be an aqueous solution or substantially an aqueous solution. By substantially aqueous solution we mean an aqueous solution which may also contain small amounts of organic or inorganic compounds, for example from solvents not completely removed after the preceding preparation steps. It will be appreciated that the process conditions (e.g., temperature) described herein may require adjustment due to the presence of small amounts of organic or inorganic impurities in order to obtain a product that can be effectively filtered, but adjustment of either process condition does not require undue experimentation by one skilled in the art.

In general, the characteristic process parameters of the invention include the temperature at which the two solutions are added and optionally the time for which the two solutions are mixed.

Typically, the mixing of the two solutions is accomplished by adding a calcium chloride solution to a pharmaceutical water-soluble salt solution. Generally, the process of adding the calcium chloride solution requires a certain time, hereinafter referred to as "addition time". When the addition of the calcium chloride solution is complete, the mixture is typically stirred for a period of time, hereinafter referred to as the "hold time". The above-mentioned mixing of the calcium chloride solution with the water-soluble salt solution for a certain period of time is understood to mean the addition time and the holding time required for mixing these solutions.

In one aspect of the invention, the addition temperature is selected to produce a product that can increase filtration efficiency.

In one embodiment, the addition is carried out at a temperature between 30 ℃ and about 45 ℃ (hereinafter referred to as "addition temperature"), preferably between 32 ℃ and 43 ℃, more preferably between 35 ℃ and 42 ℃, and most preferably at about 40 ℃. In another embodiment, the addition temperature is between 30 ℃ and 43 ℃, typically between 30 ℃ and 40 ℃.

Accordingly, in one aspect the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, the method comprises mixing a calcium chloride solution with a water soluble salt solution of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid under conditions selected to produce a product exhibiting improved filtration efficiency.

The calcium chloride solution may be heated prior to addition to the water-soluble salt solution, however it will be appreciated that heating should not cause the addition temperature to rise above 45 c and preferably not above 40 c. It is understood that the addition temperature refers to the temperature of the water-soluble salt solution.

In one aspect of the invention, the addition temperature, addition time, and hold time are selected to produce a product that can increase filtration efficiency.

In one embodiment of the invention, the addition time is from 5 to 60 minutes, in particular from 15 to 30 minutes.

In one embodiment, the holding time is at least 10 minutes. In another embodiment, the holding time is at least 15 minutes. In yet another embodiment, the holding time is at least 30 minutes. The mixture is generally stirred for a holding time at about the addition temperature. .

Accordingly, in one aspect the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, the process comprises mixing a calcium chloride solution with a water soluble salt solution of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid under conditions such that the addition temperature, addition time and holding time (all as defined above) are selected to produce a product exhibiting improved filtration efficiency.

In particular between 32 ℃ and 43 ℃ over 15-30 minutes, the mixture is kept at between 32 ℃ and 43 ℃ for at least 15 minutes, and the product is isolated by filtration and dried.

In particular, calcium chloride is added between 32 ℃ and 43 ℃ over a period of 15-30 minutes, the mixture is held between 32 ℃ and 43 ℃ for at least 30 minutes, and the product is isolated by filtration and dried.

In yet another aspect of the invention, the addition temperature and holding time are selected to produce a product exhibiting improved filtration efficiency.

In particular, the addition temperature is from 32 ℃ to 43 ℃ and the holding time is at least 30 minutes. In another aspect, the addition temperature is from 32 ℃ to 43 ℃ and the holding time is at least 15 minutes.

In yet another aspect of the invention, the addition temperature is selected to produce a product that exhibits improved filtration efficiency. In particular, the addition temperature is 32 ℃ to 43 ℃. In yet another aspect, the temperature is about 40 ℃.

In yet another aspect of the invention, the addition time is selected to produce a product that exhibits increased filtration efficiency. In particular, the addition time is 15 to 30 minutes.

In yet another aspect of the invention, the retention time is selected to produce a product that exhibits increased filtration efficiency. In particular a holding time of at least 15 minutes.

As previously mentioned, the process of the present invention results in a more efficient filtration process, such that the solid product separated on the filter contains a lower amount of water (and thus a higher "paste concentration") than the equivalent product obtained by precipitation at 20 ℃. Typically, the paste concentration obtained with the method of the invention will be greater than 45% w/w. As a result of the increased paste concentration, the final drying time after removal from the filter may be shortened, and thus the yield may be increased.

Thus in one aspect the present invention provides a process for the preparation of calcium (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoate, said process comprising contacting a calcium chloride solution with (E) -7- [4- (4-fluorophenyl) -6-isopropyl-6-enoic acid, under conditions of addition temperature, time of addition and holding time selected to produce a paste concentration of greater than 45% w/w, such as about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, about 80% w/w, about 85% w/w, about 90% w/w or about 95% w/w of the product Propyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid in water soluble salt solution.

In a further aspect the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding the calcium chloride solution to a water soluble salt solution of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid at 30-45 ℃ over 5-60 minutes, maintaining the mixture at 30-45 ℃ for at least 10 minutes, filtering, optionally washing and drying the resulting product.

In a further aspect the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding the calcium chloride solution to a water soluble salt solution of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid at 32-43 ℃ over 15-30 minutes, maintaining the mixture at 32-43 ℃ for at least 15 minutes, filtering, optionally washing and drying the resulting product.

In a further aspect the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding the calcium chloride solution to a water soluble salt solution of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid at 30-45 ℃, filtering, optionally washing and drying the resulting product.

In a further aspect the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding the calcium chloride solution to a water soluble salt solution of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid at 32-43 ℃, filtering, optionally washing and drying the resulting product.

In a further aspect the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution into water soluble salt solution of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid at 30-45 deg.C for 5-60 min, the mixture is maintained at 30-45 ℃ for at least 10 minutes, filtered, optionally washed and dried to obtain a product having a paste concentration of greater than about 45% w/w, such as about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, about 80% w/w, about 85% w/w, about 90% w/w or about 95% w/w.

In a further aspect the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution into water soluble salt solution of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid at 32-43 deg.C for 15-30 min, the mixture is maintained at 32-43 ℃ for at least 15 minutes, filtered, optionally washed and dried to obtain a product having a paste concentration of greater than about 45% w/w, such as about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, about 80% w/w, about 85% w/w, about 90% w/w or about 95% w/w.

In a further aspect the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding a calcium chloride solution to a water soluble salt solution of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid at 30-45 ℃, filtering, optionally washing and drying the resulting product, the resulting product having a paste concentration of greater than about 45% w/w, such as about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, about 80% w/w, about 85% w/w, about 90% w/w or about 95% w/w.

In a further aspect the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding a calcium chloride solution to a water soluble salt solution of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid at 32-43 ℃, filtering, optionally washing and drying the resulting product, the resulting product having a paste concentration of greater than about 45% w/w, such as about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, about 80% w/w, about 85% w/w, about 90% w/w or about 95% w/w.

In a further aspect the present invention provides a product obtainable by the process of the invention.

Another aspect of the invention provides a product obtainable by the process of the invention.

Another aspect of the invention provides a product of the process of the invention, isolated from a filter, having a paste concentration of greater than 45% w/w. Another aspect of the invention provides a product of the process of the invention, isolated from a filter, having a paste concentration of greater than 50% w/w. Another aspect of the invention provides a product of the process of the invention, isolated from a filter, having a paste concentration of greater than 70% w/w. Another aspect of the invention provides a product of the process of the invention, isolated from a filter, having a paste concentration of greater than 80% w/w. It will be understood that the term "paste concentration" is defined as the% w/w of product compound in the solid product being separated (containing a large amount of equilibrium water).

Suitable conditions for separating the product include pressure filtration or centrifugation. For example, the product may be dried by pressure filtration or centrifuge under a nitrogen stream or vacuum, or placed into a conical dryer from a separation device and dried under vacuum.

The increase in filtration efficiency achieved with the process of the invention, as described above, results in the solid product obtained, in whole or in part, possessing a different physical form than the product obtained with the processes described in the prior art. This different physical form is provided as a further aspect of the invention. It will be appreciated that the solid products obtained by the process of the invention and by the processes described in the prior art are amorphous and therefore any difference in physical form caused by the process of the invention is not due to crystallinity.

This different physical form is reflected in the increase in the particle size of the product obtained by the process of the invention. Particle size can be expressed, for example, by measuring the specific surface area of the solid by any method known in the art. The specific surface area of the product obtained by the process of the invention is generally less than about 1m²Per g (determined by the Fisher method, see, for example, Gooden, Ernest L and Smith Charles M, Inden Chem, Anal Ed.12, 479-. In contrast, the specific surface area of the products obtained with the prior art processes (at low temperatures, e.g. 20 ℃) is generally greater than or equal to about 2m²(ii) in terms of/g. It will be appreciated that the generation of a low specific surface area feedstock will generally result in a product having a higher paste concentration after a given filtration time. Alternatively, the filtration time required to achieve a certain paste concentration for a feedstock having a low specific surface area is generally short. In general, paste concentrations of at least 50% can be achieved on a laboratory scale in up to 15 minutes with the process of the invention.

In one aspect, the Specific Surface Area (SSA) as measured by the Fisher method is less than 1m²(ii) in terms of/g. In another aspect, the SSA is less than 0.9m²(ii) in terms of/g. In another aspect, the SSA is less than 0.8m²(ii) in terms of/g. In another aspect, the SSA is less than 0.7m²(ii) in terms of/g. In another aspect, the SSA is less than 0.6m²In another aspect, the SSA is less than 0.5m²(ii) in terms of/g. In another aspect, the SSA is less than 0.4m²(ii) in terms of/g. In another aspect, the SSA is less than 0.5m²(ii) in terms of/g. In another aspect, the SSA is less than 0.3m²/g。

It will be appreciated that the increase in particle size of the product obtained by the process of the invention may also result in a feedstock having beneficial properties after filtration, optional washing and drying. For example, as particle size increases, the filtered and dried material is more flowable and/or more easily comminuted and/or more easily formulated (e.g., compressed into tablets by any method known in the art).

In one aspect, the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: at a temperature selected to produce a specific surface area of less than 1m²(ii)/g (measured by Fisher's method) of the product, calcium chloride solution was mixed with (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group]Pyrimidin-5-yl]Mixing water soluble salt solution of (3R, 5S) -3, 5-dihydroxy heptyl-6-gadoleic acid.

In one aspect, the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, which process comprises generating a specific surface area of less than 0.8m at a temperature of addition selected to yield²(ii)/g (measured by Fisher's method) of the product, calcium chloride solution was mixed with (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group]Pyrimidin-5-yl]Mixing water soluble salt solution of (3R, 5S) -3, 5-dihydroxy heptyl-6-gadoleic acid.

In one aspect, the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, which process comprises generating a specific surface area of less than 0.6m at a temperature of addition selected to yield²(ii) reaction of the calcium chloride solution with (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group under conditions of yield (determined by the Fisher-Tropsch method)]Pyrimidin-5-yl]Mixing water soluble salt solution of (3R, 5S) -3, 5-dihydroxy heptyl-6-gadoleic acid.

In one aspect, the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, which process comprises generating a specific surface area of less than 0.5m at a temperature of addition selected to yield²(charge per gram)Hill method assay) with (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]Mixing water soluble salt solution of (3R, 5S) -3, 5-dihydroxy heptyl-6-gadoleic acid.

In one aspect, the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, which process comprises generating a specific surface area of less than 0.4m at a temperature of addition selected to yield²(ii) reaction of the calcium chloride solution with (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group under conditions of yield (determined by the Fisher-Tropsch method)]Pyrimidin-5-yl]Mixing water soluble salt solution of (3R, 5S) -3, 5-dihydroxy heptyl-6-gadoleic acid.

In one aspect, the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising selecting an addition temperature, an addition time and a holding time (all as defined above) to produce a specific surface area of less than 1m²(ii)/g (measured by Fisher's method) of the product, calcium chloride solution was mixed with (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group]Pyrimidin-5-yl]Mixing water soluble salt solution of (3R, 5S) -3, 5-dihydroxy heptyl-6-gadoleic acid.

In one aspect, the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising selecting an addition temperature, an addition time and a holding time (all as defined above) to produce a specific surface area of less than 0.8m²(ii)/g (measured by Fisher's method) of the product, calcium chloride solution was mixed with (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group]Pyrimidin-5-yl]Mixing water soluble salt solution of (3R, 5S) -3, 5-dihydroxy heptyl-6-gadoleic acid.

In one aspect, the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidines-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising selecting an addition temperature, an addition time and a holding time (all as defined above) to produce a specific surface area of less than 0.6m²(ii)/g (measured by Fisher's method) of the product, calcium chloride solution was mixed with (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group]Pyrimidin-5-yl]Mixing water soluble salt solution of (3R, 5S) -3, 5-dihydroxy heptyl-6-gadoleic acid.

In one aspect, the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising selecting an addition temperature, an addition time and a holding time (all as defined above) to produce a specific surface area of less than 0.5m²(ii)/g (measured by Fisher's method) of the product, calcium chloride solution was mixed with (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group]Pyrimidin-5-yl]Mixing water soluble salt solution of (3R, 5S) -3, 5-dihydroxy heptyl-6-gadoleic acid.

In one aspect, the present invention provides a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising selecting an addition temperature, an addition time and a holding time (all as defined above) to produce a specific surface area of less than 0.4m²(ii)/g (measured by Fisher's method) of the product, calcium chloride solution was mixed with (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group]Pyrimidin-5-yl]Mixing water soluble salt solution of (3R, 5S) -3, 5-dihydroxy heptyl-6-gadoleic acid.

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 30-45 deg.C]Pyrimidin-5-yl](3R, 5S) -3, 5-dihydroxyhept-6-enoic acid in a water-soluble salt solution, filtering, optionally washing and drying the resulting product to give a ratioSurface area less than 1m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 30-45 deg.C]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 0.8m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 30-45 deg.C]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 0.6m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 30-45 deg.C]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 0.5m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: dissolving calcium chloride at 30-45 deg.CAdding the solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 0.4m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 32-43 deg.C]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 1m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 32-43 deg.C]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 0.8m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 32-43 deg.C]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 0.6m²The product in g (measured by the Fisher method).

Yet another aspect of the present invention providesPreparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 32-43 deg.C]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 0.5m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 32-43 deg.C]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 0.4m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: calcium chloride solution was added to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at about 40 deg.C]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 1m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: calcium chloride solution was added to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at about 40 deg.C]Pyrimidin-5-yl]In a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acidFiltering, optionally washing and drying the product to obtain a specific surface area of less than 0.8m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: calcium chloride solution was added to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at about 40 deg.C]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 0.6m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: calcium chloride solution was added to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at about 40 deg.C]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 0.5m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: calcium chloride solution was added to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at about 40 deg.C]Pyrimidin-5-yl]Filtering, optionally washing and drying the obtained product in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid to obtain a specific surface area of less than 0.4m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]Method for preparing (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, saidThe method comprises the following steps: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 30-45 deg.C for 5-60 min]Pyrimidin-5-yl]Maintaining the mixture at 30-45 deg.C for at least 10 min in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid, filtering, optionally washing and drying the product obtained to obtain a specific surface area of less than 1m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 30-45 deg.C for 5-60 min]Pyrimidin-5-yl]Maintaining the mixture at 30-45 deg.C for at least 10 min in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid, filtering, optionally washing and drying the product obtained to obtain a specific surface area of less than 0.8m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 30-45 deg.C for 5-60 min]Pyrimidin-5-yl]Maintaining the mixture at 30-45 deg.C for at least 10 min in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid, filtering, optionally washing and drying the product obtained to obtain a specific surface area of less than 0.6m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 30-45 deg.C for 5-60 min]Pyrimidin-5-yl](3R，5In a water-soluble salt solution of S) -3, 5-dihydroxyhept-6-enoic acid, maintaining the mixture at 30-45 deg.C for at least 10 min, filtering, optionally washing and drying the resulting product to obtain a specific surface area of less than 0.5m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 30-45 deg.C for 5-60 min]Pyrimidin-5-yl]Maintaining the mixture at 30-45 deg.C for at least 10 min in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid, filtering, optionally washing and drying the product obtained to obtain a specific surface area of less than 0.4m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 32-43 deg.C for 15-30 min]Pyrimidin-5-yl]Maintaining the mixture at 32-43 deg.C for at least 15 min in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid, filtering, optionally washing and drying the product obtained to obtain a specific surface area of less than 1m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 32-43 deg.C for 15-30 min]Pyrimidin-5-yl]Maintaining the mixture at 32-43 deg.C for at least 15 min in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid, filtering, optionally washing and drying the product to obtain a specific surface areaProduct less than 0.8m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 32-43 deg.C for 15-30 min]Pyrimidin-5-yl]Maintaining the mixture at 32-43 deg.C for at least 15 min in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid, filtering, optionally washing and drying the product obtained to obtain a specific surface area of less than 0.6m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 32-43 deg.C for 15-30 min]Pyrimidin-5-yl]Maintaining the mixture at 32-43 deg.C for at least 15 min in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid, filtering, optionally washing and drying the product obtained to obtain a specific surface area of less than 0.5m²The product in g (measured by the Fisher method).

In a further aspect of the present invention there is provided a process for the preparation of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidin-5-yl]A process for the preparation of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt, said process comprising the steps of: adding calcium chloride solution to (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino group at 32-43 deg.C for 15-30 min]Pyrimidin-5-yl]Maintaining the mixture at 32-43 deg.C for at least 15 min in a water-soluble salt solution of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid, filtering, optionally washing and drying the product obtained to obtain a specific surface area of less than 0.4m²The product in g (measured by the Fisher method).

A preferred aspect of the invention provides a process comprising mixing a solution of calcium chloride with a solution of a water-soluble salt of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid, the addition temperature, addition time and holding time being adjusted to produce a product having a specific surface area which optimizes product isolation. By product isolation we mean filtration, optionally washing and drying of the product.

The products obtained by the process of the present invention can be administered in the form of conventional pharmaceutical compositions to warm-blooded animals, especially humans, in which it is desired to treat diseases involving HMG CoA reductase. Accordingly, a further aspect of the invention provides a pharmaceutical composition comprising a product obtained by the process of the invention as hereinbefore described in association with a pharmaceutically-acceptable diluent or carrier. Another aspect of the invention provides a pharmaceutical composition comprising a product obtained by the process of the invention as described above, in admixture with a pharmaceutically acceptable diluent or carrier. Suitable pharmaceutically acceptable diluents or carriers are described in our patent applications WO01/60804 and WO 01/54668.

The invention is further illustrated by, but is not limited to, the following examples.

Example 1

Preparation of methylamine salt

The experiments that generated the following data were performed as follows. (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid methylamine salt, 2M sodium hydroxide solution (0.93mol equiv.) and water were mixed together, the solution was evaporated under reduced pressure at less than 40 ℃ to a small volume to remove methylamine, and then water was added to give a concentration of the sodium salt of 0.2M. An aliquot of the stock solution was taken and calcium chloride solution (0.6mol equivalent, 0.7M aqueous solution) was added dropwise under the conditions (temperature, addition time, holding time and stirring rate) designed for the following experiment to precipitate calcium salts. Then, the reaction mixture was cooled to 20 ℃, filtered, washed three times with water, and dehydrated for a standard time before measuring the concentration of the separated raw paste.

Data of

The following data shows that the increase in paste concentration is related to temperature, addition time and holding time. These data were generated mainly when experiments were performed as part of the factorial experimental design using the methods described above.

Test number	NaOH (equivalent)	Stirring (rotating/minute)	Temperature (. degree.C.)	Adding time (minutes)	Retention time (minutes)	Concentration of paste (% w/w)
							1234567891011121314151617181920	0.990.930.960.990.990.960.930.990.960.990.930.930.930.990.930.930.990.990.960.93	550550400550550400250250400250550250550250250250550250400550	3240364040363232364032403240324032323640	1515601560156150015015150060	1010101030103030101010103030103030101030	41.4％55.9％42.7％48.7％62.9％42.4％40.5％39.5％43.3％53.9％34.8％53.9％51.6％60.79％42.9％62.0％37.0％29.1％42.9％64.6％

Example 2

Preparation at 40 ℃ from methylamine salt

Sodium hydroxide (8% w/w aqueous solution; 13.6ml) was added to a stirred mixture of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid methylamine salt (15.0 g) and water (117ml, neat). Before the methylamine was distilled off in vacuo (maximum batch temperature 40 ℃), it was washed with water (2ml, neat) in a linear fashion. Water (45ml, neat) was added and vacuum distillation was performed (maximum batch temperature 40 ℃). Water (55ml, neat) was added to the mixture before filtration through a glass fiber pad. Purified water was added to bring the total volume to the initial volume before distillation. A solution of calcium chloride dihydrate (2.58 g) in water (25ml, neat) was added dropwise over a period of 20 minutes at 40 ℃. The mixture was kept at 40 ℃ for 15 minutes, cooled to 20 ℃ over 1 hour, and then stirred at 20 ℃ before separation by filtration. The batch was washed three times with water (45ml, neat), dried under nitrogen at ambient temperature under vacuum to give amorphous (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt.

Preparation at 20 ℃ from methylamine salt

Sodium hydroxide (8% w/w aqueous solution; 13.6ml) was added to a stirred mixture of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid methylamine salt (15.0 g) and water (117ml, neat). Before the methylamine was distilled off in vacuo (maximum batch temperature 40 ℃), it was washed with water (2ml, neat) in a linear fashion. Water (45ml, neat) was added and vacuum distillation was performed (maximum batch temperature 40 ℃ C.). Water (55ml, neat) was added before filtration through a glass fiber pad. Purified water was added to bring the total volume to the initial volume before distillation. A solution of calcium chloride dihydrate (2.58 g) in water (25ml, neat) was added dropwise over a period of 20 minutes at 20 ℃. The mixture was stirred for 2 hours before separation by filtration. The solid was washed three times with water (45ml, neat), dried under nitrogen at ambient temperature under vacuum to give amorphous (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt.

The starting methylamine salt of example 1 and example 2 may be prepared as described in WO 00/49104.

Comparison of paste concentrations

The paste concentration of the sample prepared at 40 ℃ and filtered for 15 minutes was 80%. The paste concentration of the sample prepared at 20 ℃ and filtered for 15 minutes was 14%.

Example 3

Preparation at 40 ℃ from ammonium salts

To a stirred mixture of ammonium (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoate (11.7 g) and degassed water (94ml) was added sodium hydroxide (8% w/w in water; 10.9ml) at 20 ℃ and the mixture was stirred until a solution was obtained. The reaction mixture was concentrated in vacuo at less than 40 ℃ to remove ammonia, sufficient water was added to bring the total volume to the initial volume, and then the reaction mixture was heated to 40 ℃. A solution of calcium chloride dihydrate (2.1 g) in water (20ml) was added dropwise over a period of 20 minutes at about 40 ℃. The mixture was stirred for 15 minutes, cooled to 20 ℃ over 60 minutes, held at this temperature for a further 60 minutes and the resulting solid filtered. The solid was washed with water (100ml) and dried under a stream of nitrogen to give (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt in a non-crystalline state.

Preparation at 20 ℃ from ammonium salts

To a stirred mixture of ammonium (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoate (11.7 g) and degassed water (94ml) was added sodium hydroxide (8% w/w in water; 10.9ml) at 20 ℃ and the mixture was stirred until a solution was obtained. The reaction mixture was concentrated in vacuo at less than 40 ℃ to remove ammonia, sufficient water was added to bring the total volume to the initial volume, and then the reaction mixture was adjusted to 20 ℃. A solution of calcium chloride dihydrate (2.1 g) in water (20ml) was added dropwise over a period of 20 minutes at about 20 ℃. The mixture was stirred for 1.5 hours and the resulting solid was filtered. The solid was washed with water (100ml) and dried under a stream of nitrogen to give (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt in a non-crystalline state.

(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino]Pyrimidine-5- Base of]Preparation of ammonium salt of (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid

Hydrochloric acid (35ml, 0.02M) was added to a solution of tert-butyl (6- {2- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] vinyl } (4R, 6S) -2, 2-dimethyl [1, 3] dioxan-4-yl) acetate (prepared as described in WO 00/49014) (20.0g, 34.6mMol) in acetonitrile (140ml) at 35 ℃ over 100 minutes, and the temperature was maintained until the reaction was complete. The reaction mixture was cooled to 25 ℃ and then sodium hydroxide solution (1M, 38ml) was added and the reaction mixture was stirred for 1 hour. Water (100ml) was added and the acetonitrile removed in vacuo at about 40 ℃; this process is repeated, if necessary, until all the acetonitrile is removed. The mixture was filtered, n-butyl acetate (250ml) was added and the mixture was cooled to 0 ℃. The pH was adjusted to about pH3.2 with hydrochloric acid (1M, about 38 g), the mixture was stirred for about 15 minutes, and the bottom aqueous phase was removed. N-butyl acetate (250ml) was added to the organic phase and the solution was cooled to 0 ℃ again before adding a solution of ammonia in methanol (7N, 7.5 ml). The resulting mixture was heated to 30 ℃ and held at this temperature for 30 minutes after the onset of crystallization, then cooled to 0 ℃ and held at this temperature for an additional 2 hours. The solid was filtered, washed with n-butyl acetate and dried in vacuo to give the title compound (14.8 g, 86%).

Comparison of paste concentrations

After 5 minutes of filtration, the paste concentration of the filtered product was measured. The paste concentration of the sample prepared from ammonium salt at 40 ℃ was 75%. The paste concentration of the sample prepared from ammonium salt at 20 ℃ was 45%.

Example 4

Preparation at 40 ℃ from TRIS

(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid TRIS salt (17.7g) was dissolved in degassed water (120ml) at 20 ℃ and the solution was then heated to 40 ℃. A solution of calcium chloride dihydrate (2.6 g) in water (25ml) was added dropwise over a period of 20 minutes at about 40 ℃. The mixture was stirred for 15 minutes, cooled to 20 ℃ over 60 minutes, held at this temperature for a further 60 minutes and the resulting solid filtered. The solid was washed with water (140ml) and dried under a stream of nitrogen to give (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt in a non-crystalline state.

Preparation at 20 ℃ from TRIS salts

(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid TRIS salt (17.7g) was dissolved in degassed water (120ml) at 20 ℃. A solution of calcium chloride dihydrate (2.6 g) in water (25ml) was added dropwise over a period of 20 minutes at > 20 ℃. The mixture was stirred for 60 minutes and the resulting solid was filtered. The solid was washed with water (140ml) and dried under a stream of nitrogen to give (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid calcium salt in a non-crystalline state.

Preparation of TRIS salts

(E) The TRIS (hydroxymethyl) methylamine salt of (TRIS) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid (TRIS salt) can be prepared as described in WO 01/60804.

Comparison of paste concentrations

After 5 minutes of filtration, the paste concentration of the filtered product was measured. The paste concentration of the sample prepared from TRIS salt at 40 ℃ was 82%. The paste concentration of the sample prepared from TRIS salt at 20 ℃ was 36%.

Claims (18)

1. A process for the preparation of calcium (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoate, which comprises mixing a calcium chloride solution with a water-soluble salt solution of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoate, filtering, optionally washing and drying the resulting product, wherein the process parameters are selected to yield a product exhibiting improved filtration efficiency, and the characteristic process parameters include the temperature at which the two solutions are added and optionally the time for mixing the two solutions, which refers to the addition time and holding time required to mix the solutions, wherein the addition temperature is selected to be in the range of 30 ℃ to 45 ℃ to produce a product that exhibits improved filtration efficiency.

2. The method of claim 1, wherein the addition time is selected to be 5 to 60 minutes to produce a product that exhibits increased filtration efficiency.

3. The method of claim 1, wherein the retention time is selected to be at least 10 minutes to produce a product that exhibits increased filtration efficiency.

4. The method of claim 1, comprising the steps of: adding the calcium chloride solution to a water soluble salt solution of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid at 30 ℃ -45 ℃ over a period of 5-60 minutes, maintaining the resulting mixture at 30 ℃ -45 ℃ for at least 10 minutes, filtering, optionally washing and drying the resulting product.

5. The process as claimed in any of claims 1 to 4, wherein a specific surface area of less than or equal to 1m, determined by the Fisher method, is produced²Product per g.

6. The process according to claim 5, wherein a specific surface area of 0.5m or less as measured by the Fisher method is formed²Product per g.

7. The method of any one of claims 1-4, wherein the product has a paste concentration of greater than 45% w/w after filtration.

8. The method of any one of claims 1-4, wherein the concentration of the paste of the product after filtration for up to 15 minutes on a laboratory scale is at least 50% w/w.

9. The process of any of claims 1-4, wherein the resulting product after filtration has a paste concentration of greater than 70% w/w.

10. The method of any one of claims 1-4 wherein the water soluble salt of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid is an alkali metal salt.

11. The method of claim 10 wherein said water soluble salt of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid is the sodium salt.

12. The method of any one of claims 1-4, wherein the water soluble salt of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid is an ammonium salt, a methylamine salt, or a tris (hydroxymethyl) methylamine salt.

13. The process of any one of claims 1 to 4 wherein the water soluble salt of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid is prepared from an ammonium salt.

14. The method of any one of claims 1-4, wherein the water soluble salt solution is prepared from (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid or a salt thereof.

15. The method of claim 14, wherein the water soluble salt is a sodium salt.

16. The process of claim 15, wherein the sodium salt is prepared by treating an amine salt of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid with a sodium base.

17. The method of claim 16, wherein the sodium base is sodium hydroxide.

18. The process of claim 1 wherein the mixing of the two solutions is accomplished by adding a solution of calcium chloride to a water soluble salt of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] pyrimidin-5-yl ] (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid.